Protein kinases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes, maintaining control over cellular function. A partial list of such kinases includes abl, AKT, bcr-abl, Blk, Brk, Btk, c-kit, c-met, c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, GSK3α, GSK3β, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, MK2, MSK1, p38, PDGFR, PIK, PKB, PKA, PRAK, PRK2, PKC, PYK2, P70S6, ROCK2, ros, tie, tie2, TRK, Yes, and Zap70. Inhibition of such kinases has become an important therapeutic target.
Plk1 is a mitosis specific serine/threonine protein kinase that is overexpressed in a variety of human tumors. Three mammalian Plks have been identified; Plk1 is expressed during M phase and cytokinesis, whereas Plk2 (Snk) and Plk3 (Fnk) are expressed in other phases of the cell cycle. These enzymes are characterized by their similar N-terminal catalytic domains, as well as a C-terminal domain with highly conserved sequences termed the polo box. Plk1 localizes to centrosomes and the spindle poles at metaphase, in the central spindle during anaphase, and at the midbody during cytokinesis. Plk1 has been implicated in centrosome maturation, bipolar spindle formation and activation of the anaphase-promoting complex.
Plk1 phosphorylated substrates regulate four key pathways that control the coordinated progression of mitosis. Inhibiting Plk1 function using antibody injection, expression of a dominant negative Plk1, and antisense mRNA reduction produces aberrant chromosome segregation, cell cycle arrest, and mitotic cell death in tumor cell lines but reversible G2 arrest in normal nontransformed primary cell lines.
Plk1 has been shown to be overexpressed in many human tumors, such as breast, colorectal, non-small cell lung, oesophageal and ovarian cancers. It plays a central role in the regulation of the cancer cell cycle. Among other functions, Plk1 is thought to regulate initiation, progression and exit from mitosis, the stage when cancer cells divide. Consequently, blocking Plk1 in cancer cells prevents their division or mitosis. For example, the taxanes, highly successful drugs that are widely used in clinical practice to treat cancer, also work by blocking mitosis. However, these drugs cause considerable side effects upon normal, non-dividing cells especially in the nervous system. Plk inhibitor drugs specifically target dividing cells and may be able to avoid the undesirable toxicities of the taxanes. Despite the attractiveness of Plk1 as an anticancer drug target, little progress has been reported with regard to the discovery of chemical inhibitors of the Plk1 kinase.
Modulation of Plk1 by small molecules can be achieved by identifying compounds that bind to and activate or inhibit Plk1. Schwede et al. in International Publication no. WO 03/093249, published Nov. 13, 2003, disclose certain thiazolidinone derivatives and thiophene analogs as inhibitors of Plk1. Certain thiophene compounds have also been reported to inhibit Plk. Andrews et al., International Publication no. WO 03/093249, published Feb. 19, 2004.